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Article
Nature Genetics  35, 341 - 348 (2003)
Published online: 9 November 2003; | doi:10.1038/ng1267

An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis

Shinya Tokuhiro1, 2, Ryo Yamada1, Xiaotian Chang1, Akari Suzuki1, Yuta Kochi1, 3, Tetsuji Sawada3, Masakatsu Suzuki2, Miyuki Nagasaki2, Masahiko Ohtsuki2, Mitsuru Ono2, Hidehiko Furukawa2, Masakazu Nagashima4, Shinichi Yoshino4, Akihiko Mabuchi5, Akihiro Sekine6, Susumu Saito6, Atsushi Takahashi7, Tatsuhiko Tsunoda7, Yusuke Nakamura8, 9 & Kazuhiko Yamamoto1, 3

1  Laboratory for Rheumatic Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan.

2  Laboratory for Rheumatic Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), 1-7-22, Suehiro-cho, Tsurumi-ku, Sankyo, Tokyo, Japan.

3  Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

4  Department of Joint Disease and Rheumatism, Nippon Medical School, Tokyo, Japan.

5  Laboratory for Bone and Joint Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Tokyo, Japan.

6  Laboratory for Genotyping, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Kanagawa, Japan.

7  Laboratory for Medical Informatics, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Kanagawa, Japan.

8  Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.

9  Research Group for Personalized Medicine, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Tokyo, Japan.

Correspondence should be addressed to Ryo Yamada ryamada@src.riken.go.jp
Rheumatoid arthritis is a common inflammatory disease with complex genetic components. We investigated the genetic contribution of the cytokine gene cluster in chromosome 5q31 to susceptibility to rheumatoid arthritis in the Japanese population by case-control linkage disequilibrium (LD) mapping using single nucleotide polymorphisms (SNPs). Here we report that there is significant association between rheumatoid arthritis and the organic cation transporter gene SLC22A4 (P = 0.000034). We show that expression of SLC22A4 is specific to hematological and immunological tissues and that SLC22A4 is also highly expressed in the inflammatory joints of mice with collagen-induced arthritis. A SNP affects the transcriptional efficiency of SLC22A4 in vitro, owing to an allelic difference in affinity to Runt-related transcription factor 1 (RUNX1), a transcriptional regulator in the hematopoietic system. A SNP in RUNX1 is also strongly associated with rheumatoid arthritis (P = 0.00035). Our data indicate that the regulation of SLC22A4 expression by RUNX1 is associated with susceptibility to rheumatoid arthritis, which may represent an example of an epistatic effect of two genes on this disorder.

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Nature Genetics
ISSN: 1061-4036
EISSN: 1546-1718
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